The objective of this translational research grant application is to study a rare, and interesting potentially catastrophic, blistering autoimmune disease, which predominantly affects the mucous membranes known as mucous membrane pemphigoid (MMP). When it affects the oral cavity, eating and swallowing are exquisitely painful. Ocular involvement can frequently result in blindness. Since laryngeal disease can cause sudden asphyxiation and death, it mandates elective tracheostomy. Recently we described that, the anti-basement membrane zone (BMZ) antibodies found in the sera of MMP patients targets the cytoplasmic domain of human beta4 integrin. The clinical profile of mucosal involvement in MMP is variable, though the target antigen is present in all mucosae and skin. The investigator proposes to study the role of local factors involved in MMP. Using sera of patients with MMP, the investigator will identify binding of anti-BMZ antibodies to the basement membrane of the eye, nose, oral cavity, pharynx, esophagus, vagina and skin. Matching of clinical profiles with ability of patient's sera to bind to the BMZ of different mucosal tissues, or to different epitopes in the cytoplasmic domain of beta4 integrin will provide essential differences between systemic and local factors or the tissue microenvironments. The ability of sera from patients with MMP, and rabbit antibodies to bind to specific epitopes within the beta4 integrin, to produce sub-mucosal blisters in organ culture, using skin and different mucosal tissues, will be studied. Data from this study will provide important insights into how and why specific organs are involved, in a disease in which the autoantibody has the potential to cause disease in all tissues that contain the target antigen. Such advances can facilitate planning of future studies that focus on specific factors that may individually or collectively, play an important role in different organs in producing clinical disease, and this elucidate specific sites of pathology. The ability of the autoantibody to bind to specific tissues yet not produce clinical disease, might help understand and detect factors that can locally prevent disease manifestation and involvement. Such information can help generate site-specific therapy for purpose of clinical resolution and prevention of involvement. Thus MMP has the potential to be a model that could be applied to study many other multi systemic autoimmune diseases.